Atrial pacing therapy for treating mitral regurgitation

ABSTRACT

A method and apparatus are disclosed for treating mitral regurgitation with electrical stimulation. By providing pacing stimulation to the left atrium during ventricular systole, a beneficial effect is obtained which can prevent or reduce the extent of mitral regurgitation.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.11/046,132, filed Jan. 28, 2005, the specification of which is hereinincorporated by reference.

FIELD OF THE INVENTION

This invention pertains to cardiac devices such as pacemakers and othertypes of devices for treating cardiac dysfunction.

BACKGROUND

The tricuspid and mitral valves, also referred to as theatrioventricular valves, separate the atrium and ventricle on the rightand left sides of heart, respectively. The function of theatrioventricular valves is to allow flow of blood between the atrium andventricle during ventricular diastole and atrial systole but prevent thebackflow of blood during ventricular systole. The mitral valve iscomposed of a fibrous ring called the mitral annulus located between theleft atrium and the left ventricle, the anterior and posterior leaflets,the chordae tendineae, and the papillary muscles. The leaflets extendfrom the mitral annulus and are tethered by the chordae tendineae to thepapillary muscles which are attached to the left ventricle. The functionof the papillary muscles is to contract during ventricular systole andlimit the travel of the valve leaflets back toward the left atrium. Ifthe valve leaflets are allowed to bulge backward into the atrium duringventricular systole, called prolapse, leakage of blood through the valvecan result. The structure and operation of the tricuspid valve issimilar.

Mitral regurgitation (MR), also referred to as mitral insufficiency ormitral incompetence, is characterized by an abnormal reversal of bloodflow from the left ventricle to the left atrium during ventricularsystole. This occurs when the leaflets of the mitral valve fail to closeproperly as the left ventricle contracts, thus allowing retrograde flowof blood back into the left atrium. Tricuspid regurgitation (TR) occursin a similar manner. MR and TR can be due to a variety of structuralcauses such as ruptured chordae tendineae, leaflet perforation, orpapillary muscle dysfunction. Functional MR and TR may also occur inheart failure patients due to annular dilatation or myocardialdysfunction, both of which may prevent the valve leaflets from coaptingproperly.

In acute mitral valve regurgitation, the incompetent mitral valve allowspart of the ventricular ejection fraction to reflux into the leftatrium. Because the atrium and ventricle are not able to immediatelydilate, the volume overload of the atrium and ventricle results inelevated left atrial and pulmonary venous pressures and acute pulmonaryedema. The reduction in forward stroke volume due to the reflux throughthe regurgitant valve reduces systemic perfusion, which if extremeenough can lead to cardiogenic shock. In chronic mitral valveregurgitation, on the other hand, the left atrium and ventricle dilateover time in response to the volume overload which acts as acompensatory mechanism for maintaining adequate stroke volume. The leftventricular dilatation, however, may further prevent proper coaptationof the mitral valve leaflets during systolic ejection, leading toprogression of the left ventricular dilatation and further volumeoverload. Patients with compensated MR may thus remain asymptomatic foryears despite the presence of severe volume overload, but most peoplewith MR decompensate over the long term and either die or undergo acorrective surgical procedure.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B illustrate the mechanisms involved in mitralregurgitation.

FIG. 2 illustrates an exemplary implantable cardiac device.

FIGS. 3A and 3B illustrate exemplary algorithms for delivering secondaryatrial pacing.

DETAILED DESCRIPTION

The most common method presently available for definitive treatment ofMR is surgical intervention involving repair of the mitral valve orreplacement with a mechanical or transplanted valve. In order to provideearly and appropriate intervention, patients with MR may be identifiedby clinical examination and/or with specific imaging modalities such asechocardiography. The present disclosure deals with a method andapparatus for treating mitral (or tricuspid) regurgitation withelectrical pacing therapy. Pacing therapy applied in this manner may beused to treat MR either in place of or in addition to the conventionalsurgical options.

As mentioned above, one mechanism responsible for the development of MRis dilation of the left ventricle which correspondingly dilates themitral annulus and/or alters its position, thereby preventing propercoaptation of the valve leaflets. Such ventricular dilation occurs inpatients suffering heart failure or subsequent to a myocardialinfarction as a compensatory response to decreased cardiac output. Heartfailure patients may also suffer from electrical conduction deficitswhich alter the normal activation patterns of the myocardium duringsystole. Such electrical conduction deficits may result in abnormaltiming of papillary muscle contraction which also prevents properleaflet coaptation. FIGS. 1A and 1B are schematic diagrams of the leftventricle LV, left atrium LA, posterior mitral leaflet PML, anteriormitral leaflet AML, aorta AO, papillary muscle PM, and chordea tendineaeCT. FIG. 1A illustrates the normal situation during ventricular systolewhere the posterior and anterior leaflets are tethered by the chordeatendineae and papillary muscle to the posterior wall of the leftventricle in such a manner that the valve leaflets are coapted, thuspreventing reflux flow into the atrium. As the ventricle contractsfurther, corresponding contraction of the papillary muscle maintains thecoaptation of the valve leaflets and prevents them from prolapsing intothe atrium. FIG. 1B illustrates the situation where the ventricle isabnormally dilated so as to cause mitral regurgitation. The outwarddisplacement of the ventricular walls and papillary muscle causes anaugmented tethering force to be applied to the valve leaflets whichprevents proper coaptation and allows reflux flow RF into the atrium. Asthe ventricle contracts further, simultaneous contraction of thepapillary muscle maintains the augmented tethering force and preventsvalve closure.

It has been found that atrial pacing therapy may be applied in such amanner that mitral regurgitation is either prevented or lessened indegree in certain patients. In this technique, a pacing electrode isdisposed so as to excite the left atrium, e.g., either epicardially ortransvenously into the coronary sinus. If the pacing excitation is timedso as to excite the left atrium during ventricular systole, theresulting atrial contraction may cause adequate closure of an otherwiseregurgitant mitral valve. One mechanism by which this may come about isthe contraction of the region around the mitral valvular annulus duringventricular systole which then constricts the annulus and allows propercoaptation of the valve leaflets to occur. Another mechanism is that theincreased atrial pressure during systole augments the tethering force ofthe papillary muscles and thereby prevents valve prolapse.

The timing of the pacing delivered to left atrium for treating MR shouldbe such that the atrium is excited during ventricular systole. After anatrial contraction at the start of a cardiac cycle, repolarization ofthe atria normally occurs sometime during ventricular systole, and theatria are refractory to further excitation until this repolarization hastaken place. In the presently described technique for treating MR, aleft atrial pace is delivered during ventricular systole at a time aftera preceding intrinsic or paced atrial contraction sufficient for theleft atrium to have recovered from refractoriness. The atrial pacedelivered during ventricular systole is referred to herein as asecondary atrial pace as distinguished from a primary atrial pace which,in certain cardiac pacing modes, may be delivered to excite the atriumduring atrial systole and before ventricular systole. The timing of thesecondary atrial pace may be established with reference to a right orleft ventricular sense or pace such that the secondary atrial paceoccurs synchronously with a ventricular contraction. A specified delayinterval between a ventricular sense or pace and the secondary atrialpace, referred to herein as a secondary ventriculo-atrial (VA) interval,may then be specified so that the left atrium contracts during earlyventricular systole. In a patient who is not receiving ventricularpacing therapy, the secondary VA interval is initiated by a ventricularsense. In a patient who is receiving ventricular pacing therapy, thesecondary VA interval may be triggered by a ventricular sense or pace.

Alternatively, the timing of the secondary atrial pace may be referencedto an atrial sense and/or to an atrial pace if the patient is alsoreceiving atrial pacing therapy. This may be desirable in certainpatients where the optimal timing for the secondary atrial contractionin order to treat MR requires that the left atrium contract before thebeginning of electrical ventricular systole as marked by a ventricularsense or pace. In this mode, an atrio-atrio (AA) interval is specifiedas the delay interval between an atrial sense or pace and delivery ofthe secondary atrial pace.

Described below is an exemplary device which may be used to deliversecondary atrial pacing therapy to the left and/or right atria. Thedevice is configurable to also deliver conventional bradycardia orresynchronization pacing in addition to the secondary atrial pacing. Itshould be appreciated, however, that a device for delivering secondaryatrial pacing may possess only those features or components necessaryfor a particular mode of delivery.

1. Exemplary Device Description

Conventional cardiac pacing with implanted pacemakers involvesexcitatory electrical stimulation of the heart by the delivery of pacingpulses to an electrode in electrical contact with the myocardium. As theterm is used herein, a “pacemaker” should be taken to mean any cardiacdevice, such as an implantable cardioverter/defibrillator, with thecapability of delivering pacing stimulation to the heart, includingpre-excitation pacing to the mitral valve region as described herein. Apacemaker is usually implanted subcutaneously on the patient's chest,and is connected to electrodes by leads threaded through the vessels ofthe upper venous system into the heart. An electrode can be incorporatedinto a sensing channel that generates an electrogram signal representingcardiac electrical activity at the electrode site and/or incorporatedinto a pacing channel for delivering pacing pulses to the site.

A block diagram of an implantable multi-site pacemaker having multiplesensing and pacing channels is shown in FIG. 2. The controller of thepacemaker is made up of a microprocessor 10 communicating with a memory12 via a bidirectional data bus, where the memory 12 typically comprisesa ROM (read-only memory) for program storage and a RAM (random-accessmemory) for data storage. The controller could be implemented by othertypes of logic circuitry (e.g., discrete components or programmablelogic arrays) using a state machine type of design, but amicroprocessor-based system is preferable. As used herein, theprogramming of a controller should be taken to refer to either discretelogic circuitry configured to perform particular functions or to thecode executed by a microprocessor. The controller is capable ofoperating the pacemaker in a number of programmed modes where aprogrammed mode defines how pacing pulses are output in response tosensed events and expiration of time intervals. A telemetry transceiver80 is provided for communicating with an external device such as anexternal programmer. The external programmer is a computerized devicewith an associated display and input means that can interrogate thepacemaker and receive stored data as well as directly adjust theoperating parameters of the pacemaker. The telemetry transceiver 80enables the controller to communicate with an external device 300 via awireless telemetry link. The external device 300 may be an externalprogrammer which can be used to program the implantable device as wellas receive data from it or may be a remote monitoring unit. The externaldevice 300 may also be interfaced to a patient management network 91enabling the implantable device to transmit data and alarm messages toclinical personnel over the network as well as be programmed remotely.The network connection between the external device 300 and the patientmanagement network 91 may be implemented by, for example, an internetconnection, over a phone line, or via a cellular wireless link.

The embodiment shown in FIG. 2 has multiple sensing/pacing channels,where a pacing channel is made up of a pulse generator connected to anelectrode while a sensing channel is made up of the sense amplifierconnected to an electrode. A MOS switching network 70 controlled by themicroprocessor is used to switch the electrodes from the input of asense amplifier to the output of a pulse generator. The switchingnetwork 70 also allows the sensing and pacing channels to be configuredby the controller with different combinations of the availableelectrodes. The channels may be configured as either atrial orventricular channels allowing the device to deliver conventionalventricular single-site pacing, biventricular pacing, or multi-sitepacing of a single chamber, where the ventricular pacing is deliveredwith or without atrial tracking. In an example configuration, threerepresentative sensing/pacing channels are shown. A right atrialsensing/pacing channel includes ring electrode 43 a and tip electrode 43b of bipolar lead 43 c, sense amplifier 41, pulse generator 42, and achannel interface 40. A right ventricular sensing/pacing channelincludes ring electrode 23 a and tip electrode 23 b of bipolar lead 23c, sense amplifier 21, pulse generator 22, and a channel interface 20,and a left atrial sensing/pacing channel includes ring electrode 33 aand tip electrode 33 b of bipolar lead 33 c, sense amplifier 31, pulsegenerator 32, and a channel interface 30. The channel interfacescommunicate bi-directionally with a port of microprocessor 10 andinclude analog-to-digital converters for digitizing sensing signalinputs from the sensing amplifiers, registers that can be written to foradjusting the gain and threshold values of the sensing amplifiers, andregisters for controlling the output of pacing pulses and/or changingthe pacing pulse amplitude. In this embodiment, the device is equippedwith bipolar leads that include two electrodes which are used foroutputting a pacing pulse and/or sensing intrinsic activity. Otherembodiments may employ unipolar leads with single electrodes for sensingand pacing or multi-electrode leads. The switching network 70 mayconfigure a channel for unipolar sensing or pacing by referencing anelectrode of a unipolar or bipolar lead with the device housing or can60.

The controller controls the overall operation of the device inaccordance with programmed instructions stored in memory. The controllerinterprets electrogram signals from the sensing channels, implementstimers for specified intervals, and controls the delivery of paces inaccordance with a pacing mode. The sensing circuitry of the pacemakergenerates atrial and ventricular electrogram signals from the voltagessensed by the electrodes of a particular channel. An electrogramindicates the time course and amplitude of cardiac depolarization andrepolarization that occurs during either an intrinsic or paced beat.When an electrogram signal in an atrial or ventricular sensing channelexceeds a specified threshold, the controller detects an atrial orventricular sense, respectively, which pacing algorithms may employ totrigger or inhibit pacing. An impedance sensor 95 is also interfaced tothe controller for measuring transthoracic impedance. The transthoracicimpedance measurement may be used to derive either respiratory minuteventilation for rate-adaptive pacing modes or, as described below,cardiac stroke volume for modulating the delivery of secondary atrialpacing.

In order to deliver secondary atrial pacing, one or more pacing channelsare configured to secondarily pace the left atrium, each with anelectrode disposed near the region to be excited. A sensing channel forthe secondarily paced atrial site may or may not also be configured. Thecontroller is then programmed to deliver the secondary left atrial paceduring ventricular systole at a specified VA interval subsequent to aventricular sense or pace or at a specified AA interval subsequent to anatrial sense or pace. The secondary pacing of the left atrium may alsobe delivered in conjunction with ventricular resynchronization therapy.Ventricular resynchronization therapy is most commonly applied in thetreatment of patients with heart failure due to left ventriculardysfunction which is either caused by or contributed to by leftventricular conduction abnormalities. In many such patients, the leftventricle or parts of the left ventricle contract later than normalduring systole which thereby impairs pumping efficiency. In order toresynchronize ventricular contractions in these patients, pacing therapymay be applied such that the left ventricle or a portion of the leftventricle is pre-excited relative to when it would become depolarized inan intrinsic contraction. Optimal pre-excitation in a given patient maybe obtained with biventricular pacing or with left ventricular-onlypacing. In patients who are receiving ventricular resynchronizationpacing therapy, the secondary VA interval may be triggered by a sense ineither ventricle. The length of the secondary VA interval may bedifferent depending upon which type of event triggered it. For example,if a patient is receiving left ventricular pacing therapy based uponright ventricular senses, a secondary VA interval of one duration may beinitiated by a left ventricular pace while a secondary VA interval ofanother duration is triggered by a right ventricular sense.

2. Exemplary Algorithm

FIGS. 3A and 3B illustrate exemplary pacing algorithms for implementingsecondary atrial pacing to treat regurgitant AV valves which may beexecuted by an appropriately programmed controller. In FIG. 3A, thedevice waits until a ventricular sense or pace occurs at step A1. Aftera ventricular sense or pace, a software or hardware timer is started atstep A2 which defines the VA interval for delivering the secondaryatrial pace. Upon expiration of the VA interval as determined at stepA3, the secondary atrial pace is delivered at step A4. FIG. 3Billustrates an embodiment for delivering secondary atrial pacing withtiming based upon atrial events. The device waits until an atrial senseor pace occurs at step B1. After an atrial sense or pace, a software orhardware timer is started at step B2 which defines the AA interval fordelivering the secondary atrial pace. Upon expiration of the AA intervalas determined at step B3, the secondary atrial pace is delivered at stepB4.

Clinical testing (e.g., echocardiographic studies) may be employed todetermine the optimal time after the beginning of ventricular systole orafter an atrial contraction at which secondary atrial pacing should bedelivered in order to best treat a patient's MR. In the embodiment ofFIG. 3B, the AA interval is optimally set to a value which causes theatrial pace at the appropriate time during ventricular systole. Theoptimum value of the AA interval therefore depends upon the patient'sintrinsic AV interval which varies with heart rate and/or with theprogrammed paced AV delay interval which may also be programmed to varywith heart rate. In order to compensate for this, the AA interval mayalso be programmed as a function of measured or paced heart rate by,e.g., using a look-up table or a numerical formula.

A secondary pace delivered so soon after an atrial contraction that theatrium is still refractory will have no effect. It may be desirable,however, to provide a protective period following an atrial sense orpace during which an atrial secondary pace is inhibited in order toprevent pacing an atrium while it is refractory or during a vulnerableperiod. In the embodiment illustrated by FIG. 3A, this could entailinitiating the protective period upon occurrence of an atrial sense orpace. In the embodiment of FIG. 3B, it would amount to simply setting aminimum limit to which the AA interval could be set to.

3. Other Embodiments

It may be desirable in certain patients to control the delivery ofsecondary left atrial pacing so that such pacing is delivered only whenit is needed to lessen mitral regurgitation. One way in which the extentof mitral regurgitation may be monitored by an implantable device is viaa transthoracic impedance measurement reflective of cardiac strokevolume. As mitral regurgitation produces volume overloading of both theleft atrium and ventricle, such monitoring of stroke volume may be usedto modulate the frequency or duration of the secondary left atrialpacing.

The description set forth above has dealt specifically with techniquesand apparatus for treating mitral regurgitation with secondary pacing ofthe left atrium. It should be appreciated that the same techniques couldbe used to treat either mitral or tricuspid regurgitation with secondarypacing of the right or left atrium depending upon which of theatrio-ventricular valves is regurgitant. If both atrio-ventricularvalves are regurgitant, both atria may be secondarily paced with thesame or different secondary VA intervals.

Although the invention has been described in conjunction with theforegoing specific embodiments, many alternatives, variations, andmodifications will be apparent to those of ordinary skill in the art.Other such alternatives, variations, and modifications are intended tofall within the scope of the following appended claims.

1. A method comprising: identifying a regurgitant mitral or tricuspidvalve in a patient; implanting a cardiac rhythm management device in thepatient for delivering pacing therapy to the heart through one or morepacing electrodes; delivering atrial pacing therapy in a manner whichexcites an atrium during ventricular systole, referred to as secondaryatrial pacing; and, delivering the secondary atrial pacing with timingbased upon atrial events such that a secondary atrial pace is deliveredat a secondary atrio-atrio interval subsequent to an atrial event,wherein the atrio-atrio interval is selected with respect to anintrinsic or paced AV interval so that the secondary atrial pacingoccurs during ventricular systole.
 2. The method of claim 1 furthercomprising delivering primary atrial pacing therapy which paces anatrium with a primary pace to begin a cardiac cycle and wherein thesecondary atrio-atrio interval is initiated by an atrial sense orprimary pace.
 3. The method of claim 1 further comprising varying thesecondary atrio-atrio interval as a function of heart rate.
 4. Themethod of claim 3 further comprising limiting the secondary atrio-atriointerval to a specified minimum value.
 5. The method of claim 1 furthercomprising delivering ventricular pacing therapy.
 6. The method of claim5 wherein the ventricular pacing therapy is delivered as biventricularpacing.
 7. The method of claim 5 wherein the ventricular pacing therapyis delivered as left ventricle-only pacing.
 8. The method of claim 1wherein the secondary atrial pacing is delivered at multiple atrialpacing sites. 9 The method of claim 1 further comprising measuringtrans-thoracic impedance to derive a measurement reflective of cardiacstroke volume and modulating the secondary atrial pacing in accordancewith measured cardiac stroke volume.
 10. The method of claim 1 furthercomprising initiating a protective period following an atrial sense orpace during which an atrial secondary pace is inhibited.
 11. Animplantable cardiac device, comprising: pulse generating circuitrycoupled to one or more electrodes and configured to deliver pacingpulses to a cardiac chamber; sensing circuitry coupled to one or moreelectrodes and configured to detect electrical activity from a cardiacchamber; a controller coupled to the pulse generating and sensingcircuitry and configured to control the delivery of pacing pulses; and,wherein the controller is programmed to delivering pacing therapy in amanner which excites an atrium during ventricular systole, referred toas secondary atrial pacing; and, wherein the controller is furtherprogrammed to deliver the secondary atrial pacing with timing based uponatrial events such that a secondary atrial pace is delivered at asecondary atrio-atrio interval subsequent to an atrial event, whereinthe atrio-atrio interval is selected with respect to an intrinsic orpaced AV interval so that the secondary atrial pacing occurs duringventricular systole.
 12. The device of claim 11 wherein the controlleris further programmed to deliver primary atrial pacing therapy whichpaces an atrium with a primary pace to begin a cardiac cycle and whereinthe secondary atrio-atrio interval is initiated by an atrial sense orprimary pace.
 13. The device of claim 11 wherein the controller isfurther programmed to vary the secondary atrio-atrio interval as afunction of heart rate.
 14. The device of claim 13 wherein thecontroller is further programmed to limit the secondary atrio-atriointerval to a specified minimum value.
 15. The device of claim 11wherein the controller is further programmed to deliver ventricularpacing therapy.
 16. The device of claim 15 wherein the ventricularpacing therapy is delivered as biventricular pacing.
 17. The device ofclaim 15 wherein the ventricular pacing therapy is delivered as leftventricle-only pacing.
 18. The device of claim 11 wherein the controlleris further programmed to deliver the secondary atrial pacing at multipleatrial pacing sites.
 19. The device of claim 11 further comprising atrans-thoracic impedance sensor and wherein the controller is furtherprogrammed to derive a measurement reflective of cardiac stroke volumefrom the sensed trans-thoracic impedance and modulate the secondaryatrial pacing in accordance with measured cardiac stroke volume.
 20. Thedevice of claim 11 wherein the controller is further programmed toinitiate a protective period following an atrial sense or pace duringwhich an atrial secondary pace is inhibited.